While all of these likely have some role in the “missing” genetic contribution to complex diseases, examining datasets for joint effects (gene–gene or gene–environment) may prove essential in order to understand genetic associations to complex phenotypes, in spite of the computational and analytical challenges. Biology provides well-documented examples of epistasis playing an important role in phenotypes ranging from gross morphology to longevity to efficiency of reproduction (Anholt et al. 2003; Gerke et al. 2009; Mackay 2010; Vieira et al. 2000; Wolf et al. 2005). Further, many important traits of medical interest (such as heart disease, hypertension, diabetes, cancer, and infection) arise from biological systems controlled by interacting genetic factors (Churchill et al. 2004; Lander and Schork 1994; Phillips 2008; Routman and Cheverud 1995; Schork 1997; Szathmary et al. 2001).
